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EC number: 701-365-5 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Some information in this page has been claimed confidential.
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 10 May to 14 September 2006
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- Compliant to OECD 408 and GLP Guideline. Read-across from other vinyl-sulfone dye: common metabolites: The chlorinated triazine group is likely to be metabolized to cyanuric acid based groups following exposure with eventual degradation to chloride salts, ammonia, CO2 and water.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 007
- Report date:
- 2007
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Test material form:
- solid: particulate/powder
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: TOXI COOP Ltd. 1032 Budapest, Cserkesz u. 91
- Age at study initiation: 6 weeks old
- Weight at study initiation: Male: 170 -194 g; Female: 120 -152 g
- Fasting period before study: NA
- Housing: Five animals/cage
- Diet: ssniff SM R/M-Z+H complete diet for rats and mice produced by ssniff Spezialdiäten GmbH, D-59494 Soest Germany
- Water: tap ad libitum
- Acclimation period: 9 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19°C to 25°C
- Humidity (%): 30% to 70%
- Air changes (per hr): 8 to 12
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 19 May To: 14 Sep 2006
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test item was formulated in concentrations of 6.25 mg/mL, 25 mg/mL and 100 mg/mL prepared with distilled water. Formulations were prepared daily during working days and beforehand for weekends by Central Dispensary Unit of LAB International Hungary Ltd. The read across substance B was stable at the applied concentrations at room temperature for 24 hours and in refrigerator (5 ± 3 °C) for 4 days.
VEHICLE
- Concentration in vehicle: 6.25 mg/mL, 25 mg/mL and 100 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analytical control of concentration of dosing formulations was conducted on first and last weeks of the treatment. All the measured concentrations varied in the range of 92 % and 109 % of the nominal concentrations.
- Duration of treatment / exposure:
- 90 days for male animals
91 days for female animals - Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
6.25 mg/mL, 25 mg/mL and 100 mg/mL
Basis:
actual ingested
- No. of animals per sex per dose:
- 15 animals/sex in the control and high dose groups (including 5 animals/sex for recovery groups)
10 animals/sex in the low and mid dose groups - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The doses were chosen on the basis of the results of the acute oral toxicity study with the test item.
- Rationale for selecting satellite groups: reversibility of findings
- Post-exposure recovery period in satellite groups: 28 days - Positive control:
- not investigated
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: mortality & morbidity: twice daily
general clinical signs: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once prior first treatment - weekly thereafter
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule for examinations: weekly
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule and dose groups: prior to treatment - all animals
week 13 - control and high dose
HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of study and end of recovery period
- Anaesthetic used for blood collection: Yes - Euthanyl
- Animals fasted: Yes
- How many animals: all
- Parameters checked in table [3.5.1] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of study and end of recovery period
- Animals fasted: Yes
- How many animals: all
- Parameters checked in table [3.5.2] were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: for 16 hours aft termination of treatment
- Metabolism cages used for collection of urine: No data
- Animals fasted: Yes
- Parameters checked in table [3.5.3] were examined.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Day 89
- Dose groups that were examined: all animals
- Battery of functions tested:
- sensory activity
- grip strength
- motor activity
- modified Irwin - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
- Dead animal was subjected to gross pathology just after he was found dead. Terminally and at the end of the recovery period, a gross necropsy was performed on each animal just after the blood harvesting for clinical pathology examinations. One day after the last treatment, animals were sacrificed by exsanguination under pentobarbital (Euthanyl) anaesthesia. After examination of the external appearance the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs was observed. Any abnonnality was recorded with details of the location, colour, shape and size.
- Organ Weight Measurement: The following organs were weighed recorded (paired organs were weighed together):
With precision of 0.01 g: Liver, kidneys, testes, epididymides, uterus, heart, thymus, spleen, brain.
With precision of 0.001 g: Adrenals Ovaries
HISTOPATHOLOGY: Yes
- The following organs and tissues were preserved in 10% formaldehyde solution:
Gross lesions, lymph nodes (submandibular, mesenteric) sternum, skin and female mammary gland, salivary glands (submandibular), larynx, femur + bone marrow, spinal cord (cervical, lumbar, thoraeie level), pituitary, thymus, trachea, lungs (with main stern bronchi), heart, thyroid + parathyroid, oesophagus, stomaeh, caecum, duodenum, ileum, jejunum, colon, rectum, urinary bladder, liver, pancreas, spleen, kidneys, adrenals, prostate, testes with epididymides, ovaries, uterus with vagina, brain (including cerebrum, cerebellum, pons and medulla oblongata), eyes with optic nerve, Harderian glands and lachrymal gland, seminal vesicle, muscle (quadriceps), sciatic nerve, aorta.
- Full histological examinations were performed on the organs or tissues of the animals ofthe control and high dose groups. In groups 2 and 3, liver, kidneys and organs with macroscopic alteration were also processed histologically. The listed organs or their specimens were embedded into paraffin after dehydration. Slides were stained with haematoxylin eosin and examined by a light microscope. - Statistics:
- Statistical analysis was done with SPSS PC+ software package for the following data: body weight, food consumption, hematology, clinical chemistry, urinalysis, organ weight
- The heterogeneity of variance between the groups was checked by Bartlett's homogeneity of variance test. Where no significant heterogeneity was detected, a oneway analysis of variance was carried out. If the obtained result was positive, Duncan's Multiple Range test was used to assess the significance ofthe inter-group differences. Where significant heterogeneity was found, the normal distribution of data by Kolmogorov-Smimov test was used. In case of not-normal distribution, the non-parametric method of Kruskal-Wallis One-Way analysis of variance was applied.
- If positive results were obtained, the inter-group comparisons were performed using Mann-Whitney U-test. Frequency of clinical symptoms, necropsy and histopathological findings were calculated. At the end of recovery period, the homogeneity of variance between groups was determined by F-test. Depending on the result Pooled or Separate variance estimate of the Two-Sample t-test was performed. For data, which was not normally distributed, the data were compared between groups according to Mann-Whitney U-test.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- males at 1000 mg/kg
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- males at 1000 mg/kg
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- males at 1000 mg/kg
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- males at 1000 mg/kg
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- at 1000 mg/kg
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not specified
- Details on results:
- CLINICAL SIGNS AND MORTALITY
- Mortality: There was no test item related mortality. One male rat of 1000 mg/kg bw/day dose was found dead without preceding signs on day 66. Cause of death was para-gastric treatment resulting in peripheral circulatory and breathing disturbance, which is in line with the histological observation: congestion and alveolar edema causing death of animal.
- Clinical observations: 1000 mg/kg bw/day dose of read across substance B caused polyuria in male and female animals from day 2 up to the end of the treatment, which recovered 10 days after the cessation of test item administration. There were no test item related effects on animal's behavior or reaction to different type of stimuli at the functional observation battery.
BODY WEIGHT AND WEIGHT GAIN
The lower body weight gain of male animals dosed at 1000 mg/kg bw/day resulted in statistically significant body weight differences when compared to the control. The recovery groups showed increased weight gain after cessation of treatment, which is a typical response to non-specific toxicity. The body weight change in males at 1000 mg/kg was considered to be an effect of treatment, although all weights were within the normal range.
FOOD CONSUMPTION
There were no differences in the mean food consumption between any dose levels except weeks 9 and 10 in male 1000 mg/kg bw/day dose, where statistically significantly less food intake was measured.
WATER CONSUMPTION
Water consumption was not measured. But the routine control of animals showed a hiher water consumption in high-dose animals. The bottle size was therefore increased to 1000 mL bottles for this group.
OPHTHALMOSCOPIC EXAMINATION
No effects observed
HAEMATOLOGY
There were no toxicologically significant test item induced alterations in the examined haematological parameters at termination of the treatment.
CLINICAL CHEMISTRY
There were no test item re1ated differences in the examined biochemical parameters.
URINALYSIS
A test item influence on the urine excretion was observed in all groups, which manifested in an elevated volume of urine at 62.5 mg/kg bw/day (no statistical significance in male group), 250 mg/kg bw/day, and 1000 mg/kg bw/day and in a decreased specific gravity at 250 mg/kg bw/day male and at 1000 mg/kg bw/day (male and female animals). Although the effect was related to treatment, it was considered to be a physiological effect, related to the high salt level in the test item, and not an adverse effect of treatment.
NEUROBEHAVIOUR
There were no differences related to the test item in the examined parameters.
ORGAN WEIGHTS
No test item related differences were noted in the weighed organs of test groups.
GROSS PATHOLOGY
No test item related macroscopic findings were detected at the necropsy.
Dead animal : Dark red lungs, blood filled thoracic cavity and yellow colour of the organs were noted for the rat which died from misgavage.
HISTOPATHOLOGY: NON-NEOPLASTIC
There were no test item related lesions in the organs of animals subjected to histopathological examination.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: 1000 mg/kg bw/day: - increased water consumption and urine excretion due to a high salt concentration (lithium and sodium) in the test substance - minimally reduced body weight gain and food consumption in males
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- The read across substance B caused an increased water consumption and urine excretion in the course of 90-day consecutive oral administration at 1000 mg/kg bw/day dose level to CRL:(WI) BR rats, which recovered within 10 days after cessation of the treatment. This effect was ascribed to high levels of salts in the test item (lithium and sodium) and is considered to be a physiological response and not an adverse toxic effect.
The body weight and food consumption was slightly depressed in male group of 1000 mg/kg bw/day. This reversed in the recovery phase.
Urinalysis revealed a higher volume of urine at 62.5 mg/kg bw/day, 250 mg/kg bw/day and 1000 mg/kg bw/day after 16 hours collection at termination of the treatment. The increased volume of urine indicates an increased physiological function without any related pathologie (clinical or histopathology) alterations.
The changes observed at 1000 mg/kg were minor in nature and were reversible. There were no signs of serious irreversible toxicity at 1000 mg/kg bw/day.
The no observed adverse effect level (NOAEL) of the read across substance B was 250 mg/kg bw/day. - Executive summary:
In a GLP-compliant study performed according to OECD guideline 408, a 90-day repeated dose oral (gavage) toxicity study was performed in CRL:(WI) BR rats (n= 10 animals/sex/group and further 5 animals/sex in the control and Group 4 for recovery) on the read-across substance with dose levels of 0 (vehicle only), 62.5, 250 and 1000 mg/kg bw/day. Animals were treated by daily oral gavage with test item or vehic1e (distilled water) at a constant dosing volume of 10 mL/kg body weight. Recovery animals were retained for further 28-day observation without treatment.
The stability of test item in this vehicle was found to be adequate (at least 24 hours at room temperature and at least 4 days at 5 ± 3 °C.) General clinical observations were made daily and detailed clinical observations were performed weekly. A functional observation battery was conducted on week 13. Body weight and food consumption were measured weekly. Ophthalmoscopy was made on all animals before starting of the treatment and in the control and high dose groups on week 13. Urinalysis was conducted on week 12, clinical pathology and gross pathology one day after the last treatment. Selected organs were weighed. A full histological examination was performed on the preserved organs and tissues of the animals of the control group and Group 4 (1000 mg/kg bw/day). The liver, kidneys and organs with macroscopic findings were evaluated histologically in Group 2 and Group 3. Animals of recovery groups were processed in the same manner at termination of the recovery period.
Results
Mortality:
There was no test item related mortality. One male rat of 1000 mg/kg bw/day dose was found dead without preceding signs on day 66. Cause of death was para-gastric treatment resulting in peripheral circulatory and breathing disturbance, which is in line with the histological observation: congestion and alveolar edema causing death of animal.
Clinical observations:
1000 mg/kg bw/day dose of read-across substance caused polyuria in male and female animals from day 2 up to the end of the treatment, which recovered 10 days after the cessation of test item administration. There were no test item related effects on animal's behavior or reaction to different type of stimuli at the functional observation battery.
Body weight:
The mean body weight gain of male animals at 1000 mg/kg bw/day was less than the control value during the treatment period resulting in significant difference in the body weight, which was not reversible at the end of the recovery period.
Food consumption:
There were no differences in the mean food consumption between any dose levels except weeks 9 and 10 in males of the 1000 mg/kg bw/day dose, where significantly less food intake was measured.
Clinical pathology:
There were no test item related adverse effects of treatment in the examined hematological or clinical chemistry parameters. A higher volume of the urine was noted for 62.5 mg/kg bw/day, 250 mg/kg bw/day and 1000 mg/kg bw/day doses at the terminal urinalysis.
Gross pathology:
No test item related macroscopic finding were found at the necropsy.
Organ weight:
There were no relevant test item organ weight alterations (male and female).
Histopathology:
There were no histopathological changes related to the test item effect detected.
Conclusions
The read-across substance caused an increased water consumption and urine excretion in the course of 90 -day consecutive oral administration at 1000 mg/kg bw/day dose level to CRL:(WI) BR rats, which recovered within 10 days after cessation of the treatment. This effect was ascribed to high levels of salts in the test item (lithium and sodium) and is considered to be a physiological response and not an adverse toxic effect.
The body weight and food consumption was slightly depressed in male group of 1000 mg/kg bw/day. This reversed in the recovery phase.
Urinalysis revealed a higher volume of urine at 62.5 mg/kg bw/day, 250 mg/kg bw/day and 1000 mg/kg bw/day after 16 hours collection at termination of the treatment. The increased volume of urine indicates an increased physiological function without any related pathologie (clinical or histopathology) alterations.
The changes observed at 1000 mg/kg were minor in nature and were reversible. There were no signs of serious irreversible toxicity at 1000 mg/kg bw/day.
The no observed adverse effect level (NOAEL) of the read-across substance was 250 mg/kg bw/day.
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